C57BL/10 and BALB/c mice differ in their abilities to clear infections with the intracellular bacterium Brucella abortus strain 2308. We have previously reported that in vivo of IL-10 in the susceptible BALB/c mice results in significantly fewer bacteria in their spleens 1 week after infection with 5 x 10(3) colony forming units (CFU) of 2308. Here we extend those studies and report a similar effect when IL-4 is neutralized. In contrast, in the more resistant C57BL/10 mice infected with 5 x 10(3) CFU, neither neutralization of IL-4 significantly decreased the level of infection nor did it in either BALB/c or C57BL/10 mice infected with a 1000-fold higher dose of strain 2308. While splenocytes from the later mentioned groups of mice produced IL-10 in response to stimulation with brucella antigen, they also produced higher levels of interferon (IFN)-gamma than those from BALB/c mice with the low challenge dose of 5 x 10(3) CFU. Results of in vivo neutralization of IFN-gamma by monoclonal antibodies (MAb) reported here and elsewhere indicated that IFN-gamma is important for control; thus, we postulate that the higher levels of IFN-gamma override the detrimental effects of Th2 cytokines. In vitro studies also showed that macrophages from the more resistant C57BL/10 mice were less susceptible to the ability of IL-10 to decrease anti-brucella activities than were BALB/c macrophages. CD4+ T cells were principally responsible for the production of IL-10 in BALB/c but not C57BL/10 splenocyte populations. C57BL/10 splenocytes produced more IFN-gamma than those from BALB/c mice in response to stimulation with brucella antigens. These differences between BALB/c and C57BL/10 mice may contribute to the superior capacity of C57BL/10 mice to control infections with B. abortus strain 2308.